Method of treating a peripheral neuropathic pain

ABSTRACT

The invention provides methods for treating and preventing neuropathic pain which comprise the administration of an effective amount of an antagonist of the pain-enhancing effects of E-type prostaglandins, for example, EP 1 -typo prostaglandin receptor antagonists, to warm-blooded animals including humans in need of such treatment. The invention also provides pharmaceutical compositions for such prevention and treatment of neuropathic pain.

This application is the National Phase of International ApplicationPCT/GB00/00439 filed Feb. 11, 2000 which designated the U.S. and thatInternational Application.

This invention relates to therapeutic agents, and in particular to theuse of compounds that are antagonists of the pain enhancing effects ofE-type prostaglandins for the treatment or prevention of neuropathicpain. The invention also concerns the use of a compound that is anantagonist of the pain enhancing effects of E-type prostaglandins in theproduction of a medicament for use in the treatment or prevention ofneuropathic pain. The invention further concerns a method of treating orpreventing neuropathic pain by administration of an effective amount ofan antagonist of the pain enhancing effects of E-type prostaglandins toa warm blooded animal such as man.

Neuropathic pain is a common clinical symptom associated with a varietyof peripheral neuropathies and central nervous system injuries.Peripheral nerve injuries can arise directly from trauma, or indirectlyfrom a wide range of diseases such as infections, cancer, metabolicconditions, toxins and musculoskeletal changes. Central nervous systeminjuries associated with neuropathic pain include stroke, trauma,Parkinson's disease, multiple sclerosis and syringomyelia. The symptomsand signs of neuropathic pain include spontaneous/continuous pain,heightened cutaneous sensitivity (hyperesthesia), increased sensitivitywith a lowering of the threshold to noxious stimulation (hyperalgesia),continued sensation of pain after the stimulus has ceased (hyperpathia),nociceptive response to innocuous stimulation (allodynia) and thepresence of sensory deficits (hypoalgesia).

The treatment of neuropathic pain represents a significant therapeuticchallenge Current clinical practice includes the use of a number of drugclasses for the management of neuropathic pain, for exampleanticonvulsants, tricyclic antidepressants, and systemic localanaesthetics. However, the usual outcome of such treatment is partial orunsatisfactory pain relief, and in some cases the adverse effects ofthese drugs outweigh their clinical usefulness.

Classic analgesics are widely believed to be poorly effective orineffective in the treatment of neuropathic pain. Few clinical studieson the use of non steroidal anti-inflammatory drugs (NSAIDs) or opiatesin the treatment of neuropathic pain have been conducted, but in thosewhich have, the results appear to indicate that NSAIDs are poorlyeffective or ineffective and opiates only work at high doses. A reviewanalysing the controlled clinical data for peripheral neuropathic pain(PNP) (Pain, November, 1997 73(2), 123-39) reported that NSAIDs wereprobably ineffective as analgesics for PNP and that there was nolong-term data supporting the analgesic effectiveness of any drug.

The development of a rodent model of peripheral mononeuropathy (Pain,33, 1988, 87-107; Exp Brain Res, 113, 1997, 200-206; and Exp Brain Res,120, 1998, 432-438) has provided a new approach for studies ofpost-injury neuropathic pain. The model produces neuropathic painsyndromes in the rat by loosely ligating the common sciatic nerve andhas been described as a chronic constrictive injury (CCI) model. Thebehavioural, morphological and autoradiographic data obtained from therodents in this model closely represent the clinical features ofpost-injury neuropathic pain. For example, the anticonvulsant gabapentindemonstrates activity in the CCI model (Eur J Pharmacol, 324, 1997,157-160) and has been evaluated against neuropathic pain in humans(JAMA. 280, 1998, 1837-42; Clin J Pain. 13, 1997, 251-5). The NSAIDketorolac tromethamine possessed modest activity compared to morphinewhen dosed intrathecally (Can J Anaesth, 1996, 43, 967). This model hasvalue therefore in predicting efficacy of compounds against neuropathicpain.

This invention is based on the surprising discovery that compounds knownto be antagonists of the pain enhancing effects of E-type prostaglandinshave activity in the CCI model.

According to the invention, there is provided a method of treating orpreventing neuropathic pain in a warm blooded animal such as a humanbeing requiring such treatment which comprises administering to saidanimal a therapeutically effective amount of an antagonist of the painenhancing effects of E-type prostaglandins, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof.

Typical antagonists of the neuropaihic pain enhancing effects of E-typeprostaglandins useful in this invention include the following E₁-typeprostaglandin receptor antagonists.

a) 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylicacid (disclosed as Example 15 in International Patent Application WO96/03380);

b)6-[N-(5-bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylicacid (disclosed as Example 15 in International Patent Application WO97/00864);

c)N-propanesulphonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide(disclosed as Example 14 in International Patent Application WO97/00863);

d)N-(3,5-dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide(disclosed as compound number 1 in Example 8 in International PatentApplication WO 97/00863); and

e)6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazine-3-carboxylicacid (disclosed as Example 3 in International Patent Application WO97/00863);

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.

According to a further feature of the invention, there is provided amethod of treating or preventing neuropathic pain in a warm bloodedanimal such as a human being requiring such treatment which comprisesadministering to said animal a therapeutically effective amount of acompound listed under paragraphs a)-e) above, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof.

According to a further feature of the invention, there is provided amethod of treating or preventing neuropathic pain in a warm bloodedanimal such as a human being requiring such treatment which comprisesadministering to said animal a therapeutically effective amount of thecompound listed under paragraph c) above, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof.

Further antagonists of the pain enhancing effects of E-typeprostaglandins include those described in EP 0480641; EP 0534667; WO96/03380; WO 96/06822; EPA 0733033; EPA 0847391; EPA 0835246 and EPA0752421. The contents of the aforesaid European and International PatentApplications are hereby incorporated by reference thereto.

In addition antagonists of the pain enhancing effects of E-typeprostaglandins include those described in U.S. Pat. No. 5,504,077; EP694546; U.S. Pat. No. 5,441,950; U.S. Pat. No. 5,420,270; U.S. Pat. No.5,354,747; U.S. Pat. No. 5,354,746; U.S. Pat. No. 5,324,722; U.S. Pat.No. 5,304,644; U.S. Pat. No. 5,281,590; WO 9313082; EP 539977; WO9307132; EP 512400; EP 512399; EP 218077; EP 193822; U.S. Pat. No.4,132,847; EP 0878465; EP 0300676; U.S. Pat. No. 4,775,680; EP 0845451;EP 0160408; U.S. Pat. No. 4,820,689 and WO 9827053. The contents of theaforesaid US, European and International Patents and Applications arehereby incorporated by reference thereto.

According to a further aspect of the invention there is provided the useof a compound that is an antagonist of the pain enhancing effects ofE-type prostaglandins, or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof, for the manufacture of a medicament foruse in the treatment or prevention of neuropathic pain.

According to a further aspect of the invention there is provided the useof a compound that is an antagonist of the pain enhancing effects ofE-type prostaglandins for the treatment or prevention of neuropathicpain.

According to a further aspect of the invention there is provided the useof a compound that is an antagonist of the pain enhancing effects ofE-type prostaglandins or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof, for the treatment or prevention ofneuropathic pain.

According to a further aspect of the invention there is provided the useof a compound listed under paragraphs a)-e) above, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, for themanufacture of a medicament for use in the treatment or prevention ofneuropathic pain.

According to a further aspect of the invention there is provided the useof a compound listed under paragraphs a)-e) above or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, for thetreatment or prevention of neuropithic pain.

According to a further aspect of the invention there is provided the useof the compound listed under paragraph c) above or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, for themanufacture of a medicament for use in the treatment or prevention ofneuropathic pain.

Preferred compounds of the invention are those listed under paragraphsa)-e) above, or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof.

A particularly preferred compound is the compound listed under paragraphabove, or a pharmaceutically acceptable salt or an in vivo hydrolysableester thereof.

Preferred aspects of the invention relate to the uses and methodsdescribed above of the compound or a pharmaceutically acceptable saltthereof.

In cases where compounds of the invention are sufficiently basic oracidic to form stable acid or basic salts, administration of thecompound as a salt may be appropriate, and pharmaceutically acceptablesalts may be made by conventional methods such as those described below.Examples of suitable pharmaceutically acceptable salts are organic acidaddition salts formed with acids which form a physiologically acceptableanion, for example, tosylate, methanesulphonate, acetate, tartrate,citrate, succinate, benzoate, ascorbate, maleate, α-ketoglutarate, andα-glycerophosphate. Suitable inorganic salts may also be formed such assulphate, nitrate, hydrochloride and hydrobromide.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound (or its ester) with a suitable acid affording aphysiologically acceptable anion. It may also be possible to make acorresponding alkali metal (e.g. sodium, potassium, or lithium) oralkaline earth metal (e.g. calcium) salt by treating a compound of theinvention (and in some cases the ester) with one equivalent of an alkalimetal or alkaline earth metal hydroxide or alkoxide (e.g. the ethoxideor methoxide) in aqueous medium followed by conventional purificationtechniques.

An in vivo hydrolysable ester of a compound of the invention containinga carboxy group is, for example, a pharmaceutically acceptable esterwhich is hydrolysed in the human or animal body to produce the parentacid, for example, a pharmaceutically acceptable ester formed with aC₁₋₆alcohol such as methanol, ethanol, ethylene glycol, propanol orbutanol, or with a phenol or benzyl alcohol such as phenol or benzylalcohol or a substituted phenol or benzyl alcohol wherein thesubstituent is, for example, a halo (such as fluoro or chloro),C₁₋₄alkyl (such as methyl) or C₁₋₄alkoxy (such as ethoxy) group. Theterm also includes α-acyloxyalkyl esters and related compounds whichbreak down to give the parent hydroxy group. Examples of α-acyloxyalkylesters include acetoxymethoxycarbonyl and2,2-dimethylpropionyloxymethoxycarbonyl.

In use, an antagonist of the pain enhancing effects of E-typeprostaglandins, or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof, will generally be administered for itstreatment or prevention of neuropathic pain in a warm-blooded animalsuch as man requiring such treatment, in the form of a conventionalpharmaceutical composition, for example, as may be described in therelevant published European, US or International patent applicationsreferred to above, and generally the composition may be in a formsuitable for oral administration, for example as a tablet or capsule,for parenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) for example as a sterilesolution, suspension or emulsion, for topical administration for exampleas an ointment or cream or for rectal administration for example as asuppository. In general the above compositions may be prepared in aconventional manner using conventional excipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremetre body area of the animal, i.e. approximately 0.1-100 mg/kg. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1-500 mg of active ingredient.

Therefore according to a further feature of the invention there isprovided a pharmaceutical composition which comprises an antagonist ofthe pain enhancing effects of E-type prostaglandins or apharmaceutically acceptable salt or an in vivo hydrolysable esterthereof, in association with a pharmaceutically acceptable excipient orcarrier for the treatment or prevention of neuropathic pain.

The identification of compounds which are useful in the treatment orprevention of neuropathic pain is the subject of the present invention.These properties may be assessed, for example, using the CCI model asdescribed in Pain, 33, 1988, 87-107.

In that model, the compound described in paragraph d) above demonstratesactivity at oral test doses of 0.3, 3 and 30 mg/kg/day (dosed four timesa day).

Antagonists of the pain enhancing effects of E-type prostaglandins maybe used in the treatment or prevention of neuropathic pain in singletherapeutic agent therapy or in combination therapy. Combination therapymay involve current conventional therapeutic agents used in themanagement of neuropathic pain such as anticonvulsants, tricyclicantidepressants and systemic local anaesthetics. Combination therapy mayalso involve the use of a locally applied local anaesthetic.

Combination therapy may also involve conventional NSAIDs such asindomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac,tolmetin and piroxicam or COX-2 inhibitors such as celecoxib orrofecoxib. Combination therapy may also involve an opiate.

For the avoidance of doubt, where the treatment or prevention ofneuropathic pain is referred to, this includes the associated symptomsand signs of neuropathic pain. The neuropathic pain may also be ofcentral or peripheral origin.

What is claimed is:
 1. A method of treating a peripheral neuropathicpain in a warm-blooded animal requiring such treatment which comprisesadministering to said animal a therapeutically effective amount of anEP₁-type prostaglandin receptor antagonist selected from the groupconsisting of:6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylicacid;6-[N-(5-bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylicacid;N-propanesulphonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl-N-ethylamino]pyridazin-3-carboxamide;N-(3,5-dimethylisoxazol-4-ylsulphonyl)-6-[N-(5-chloro-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridazin-3-carboxamide;6-[N-(5-bromo-2-(cyclopropylmothoxy)benzyl)-N-ethylamino]pyridazine-3-carboxylicacid; and pharmaceutically acceptable salts and in vivo hydrolysableesters thereof.
 2. The method according to claim 1 wherein the EP₁-typeprostaglandin receptor antagonist isN-propanesulphonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl-N-ethylamino]pyridazine-3-carboxamide,or a pharmaceutically acceptable salt or in-vivo hydrolysable esterthereof.
 3. A method according to claim 1, wherein the peripheralneuropathic pain is a post-injury peripheral neuropathic pain.